Gamma tocotrienol in the war on cancer

A flurry of recent studies demonstrates that gamma tocotrienol, a unique form of vitamin E, offers protection at the molecular level from a number of different types of cancer.
Breast Cancer¹ – A study showed that gamma tocotrienol, at levels of dietary supplement intake, reduced the spreading of breast cancer cells by 58%.
Prostate Cancer² – A study showed that gamma tocotrienol was able to kill prostate cancer cells by modulating gene signals, including reduction of the key pro-inflammatory gene signal, NF-kappaB .  Additionally, it was found to modulate other genes that inhibited the ability of the prostate cancer cells to spread, meaning that in addition to killing prostate cancer cells it was able to reduce their invasiveness.
Stomach Cancer³ – A study showed that gamma tocotrienol induced cell death and prevented cell metastasis of stomach cancer cells.  The authors concluded, “These findings suggest a potential mechanism of gamma-tocotrienol-mediated antitumor metastasis activity and indicate the role of vitamin E as potential chemopreventative agents against gastric cancer.” 
Colon Cancer – A study showed that gamma tocotrienol could knock out colon cancer cells.  Once again, part of the mechanism of action was a potent reduction of the inflammatory gene signal NF-kappaB .
Malignant Melanoma⁵ – Skin cancer is a major concern for many.  A new study shows that gamma tocotrienol can kill melanoma cells, primarily by reducing NF-kappaB and related gene signals.  It also reduced gene signals associated with invasiveness.  And it also helped chemo drugs work better, consistent with earlier findings of synergistic benefit.
While no person should consider any one vitamin a treatment or prevention of cancer, this data clearly shows that gamma tocotrienol is a powerful tool working in your favor.

 Byron J. Richards,
Board Certified Clinical Nutritionist 

 http://www.wellnessresources.com/health/articles/gamma_tocotrienol_in_the_war_on_cancer/

 Referenced Studies:

1. ^ Gamma Tocotrienol, Resveratraol, and Breast Cancer  Int J Oncol.  Hsieh TC, Wu JM.
2. ^ Gamma Tocotrienol and Prostate Cancer  Br J Cancer.   Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL.
3. ^ Gamma Tocotrienol and Gastric Cancer  J Nutr Biochem.   Liu HK, Wang Q, Li Y, Sun WG, Liu JR, Yang YM, Xu WL, Sun XR, Chen BQ.
4. ^ Gamma Tocotrienol and Colon Cancer  Nutrition.  Xu WL, Liu JR, Liu HK, Qi GY, Sun XR, Sun WG, Chen BQ.
5. ^ Gamma Tocotrienol and Malignant Melanoma  Nutr Cancer.  Chang PN, Yap WN, Lee DT, Ling MT, Wong YC, Yap YL. 

Hsieh TC, Wu JM. Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and gamma-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells. Int J Oncol.  2009 October  33(4):851-9.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.

Study Abstract:

Numerous dietary phytochemicals have shown anti-breast carcinogenic activities when tested in vitro; however, in most cases, the demonstrated efficacy of individual phytochemicals requires doses not readily achievable in vivo. Therefore, whether diets might exert translational promises and benefits in clinical settings and prevention of breast cancer remain unclear. Since cancer cells are endowed with complex, redundant, converging and diverging pathways spanning both the genetic and metabolic networks that are not merely replicates of those in normal cells, it is of interest to test whether a multicomponent approach involving lower, physiologically relevant doses of natural dietary agents may be developed as a chemopreventive strategy for breast cancer. Herein, we investigated, using the estrogen receptor-positive MCF-7 breast cancer cells as a model, whether the combination of epigallocatechin gallate (EGCG), resveratrol and gamma-tocotrienol at suboptimal doses elicits synergism in suppressing cell proliferation, modulating gene expression, and increasing antioxidant activity, as compared to each of the three phytochemicals added alone. The results showed that there was a approximately 33, 50 and 58% inhibition of cell proliferation by > or =50 microM EGCG, > or =25 microM resveratrol and > or =10 microM gamma-tocotrienol, respectively, added as a single agent. When a suboptimal dose (10 microM) of each phytochemical was used, a significant additive effect in suppression of cell proliferation was observed with the combination of resveratrol and gamma-tocotrienol whereas the three phytochemicals added together did not produce more pronounced inhibition of cell proliferation. A significant additive effect in reducing cyclin D1 and bcl-2 expression was found when gamma-tocotrienol was added with either EGCG or resveratrol. Functional synergism among the three phytochemicals was only observed in the induction of quinone reductase NQO1. These results suggest that diet-based protection against breast cancer may partly derive from synergy amongst dietary phytochemicals directed against specific molecular targets in responsive breast cancer cells, and provide support for the feasibility of the development of a diet-based combinatorial approach in the prevention and treatment of breast cancer.

 Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL. Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br J Cancer.   2008 December  99(11):1832-41.
Davos Life Science Pte. Ltd., Cancer Research Laboratory, 11 Biopolis way, #07-03, The Helios 138667, Singapore.

Study Abstract:

Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

Liu HK, Wang Q, Li Y, Sun WG, Liu JR, Yang YM, Xu WL, Sun XR, Chen BQ. Inhibitory effects of gamma-tocotrienol on invasion and metastasis of human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem.   2009 February
Department of Nutrition and Food Hygiene, Public Health School, Harbin Medical University, NanGang District, Harbin, Heilongjiang Province 150086, People's Republic of China.

Study Abstract:

Natural vitamin E is a mixture of two classes of compounds, tocopherols and tocotrienols. Recent research has revealed that tocotrienols, especially gamma-tocotrienol, exhibit not only the same antioxidant ability as tocopherols, but also remarkable anticancer capacity in cancer cell lines. In this study, the invasion and metastatic capacities of gastric adenocarcinoma SGC-7901 cells and the correlation with antimetastasis mechanisms induced by gamma-tocotrienol were explored. The results showed the inhibitory effects of gamma-tocotrienol at doses of 15, 30, 45 and 60 mumol/L for 48 h on cell migration and cell matrigel invasion; activities of matrix metalloproteinase (MMPs) increased in SGC-7901 cells when compared to the control group (P<.05 or P<.01). An increasing trend in the chemotactic responses to fibronectin (FN) in SGC-7901 cells was found in the gamma-tocotrienol treatments. SGC-7901 cell attachment decreased in the gamma-tocotrienol-treated groups in comparison with the control group (P<.01). The mRNA expressions of MMP-2 and MMP-9 showed that gamma-tocotrienol significantly reduced the matrigel invasion capability through down-regulation of the mRNA expressions of MMP-2 and MMP-9 (P<.01), and up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 in SGC-7901 cells by treatment with gamma-tocotrienol for 48 h (P<.05). gamma-Tocotrienol also significantly increased the mRNA expression of nm23-H1 in SGC-7901 cells (P<.01). These findings suggest a potential mechanism of gamma-tocotrienol-mediated antitumor metastasis activity and indicate the role of vitamin E as potential chemopreventative agents against gastric cancer.

 Xu WL, Liu JR, Liu HK, Qi GY, Sun XR, Sun WG, Chen BQ. Inhibition of proliferation and induction of apoptosis by gamma-tocotrienol in human colon carcinoma HT-29 cells. Nutrition.  2009 May  25(5):555-66.
Department of Nutrition and Food Hygiene, Public Health School, Harbin Medical University, Harbin, People's Republic of China.

Study Abstract:

OBJECTIVE: gamma-Tocotrienol is a major component of the tocotrienol-rich fraction of palm oil, but there is limited evidence that it has antitumor activity. In particular, the effects of gamma-tocotrienol on human colon carcinoma cells have not been reported. To investigate the chemopreventive effects of gamma-tocotrienol on colon cancer, we examined its capacity to inhibit proliferation and induce apoptosis in HT-29 cells and explored the mechanism underlying these effects.
METHODS: We cultured HT-29 cells in the presence of gamma-tocotrienol. The effect of gamma-tocotrienol on cell proliferation was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, mitotic index, and colony formation. The cell-cycle distribution was investigated by flow cytometry. We measured apoptosis by nuclear staining, transmission electron microscopy, and DNA fragmentation. Apoptosis-related proteins and the nuclear factor-kappaB p65 protein were determined by western blotting and immunofluorescence.
RESULTS: gamma-Tocotrienol inhibited cell growth and arrested HT-29 cells in G(0)/G(1) phase. The 50% inhibitory concentration was 31.7 micromol/L (48 h). gamma-Tocotrienol-induced apoptosis in HT-29 cells was accompanied by downregulation of Bcl-2, upregulation of Bax, and activation of caspase-3. Furthermore, we found that gamma-tocotrienol reduced the expression level of total nuclear factor-kappaB p65 protein and inhibited its nuclear translocation.
CONCLUSION: The results indicated that gamma-tocotrienol inhibits cell proliferation and induces apoptosis in HT-29 cells in a time- and dose-dependent manner, and that this process is accompanied by cell-cycle arrest at G(0)/G(1), an increased Bax/Bcl-2 ratio, and activation of caspase-3. Our data also indicated that nuclear factor-kappaB p65 protein may be involved in these effects.

Chang PN, Yap WN, Lee DT, Ling MT, Wong YC, Yap YL. Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells. Nutr Cancer.  2009 June  61(3):357-66.
Davos Life Science Pte. Ltd., Cancer Research Laboratory, 138667, Singapore

Study Abstract:

To date, the most effective cure for metastatic melanoma remains the surgical resection of the primary tumor. Recently, tocotrienol-rich-fraction has shown antiproliferative effect on cancer cells. To elucidate this anticancer property in malignant melanoma, this study aimed, first, to identify the most potent isomer for eliminating melanoma cells and second to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of procaspases and the accumulation of sub-G1 cell population. Examination of the prosurvival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R, and Id family proteins. Meanwhile, gamma-tocotrienol treatment also resulted in induction of JNK signaling pathway, and inhibition of JNK activity by selective inhibitor was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, synergistic effect was observed when cells were cotreated with gamma-tocotrienol and chemotherapy drugs. Together, our results demonstrated for the first time the anti-invasion and chemonsensitization effect of gamma-tocotrienol against human malignant melanoma cells.